Hepatitis B virus (HBV) infection is a worldwide health problem. It is estimated that there are 200 to 500 million HBV chronic carriers in the world for whom, to date, there is no reliable treatment. HBV causes both acute and chronic liver disease and the estimated relative risk of primary hepatocellular carcinoma (PHC) in chronic HBV carriers is approximately 100 times greater than in uninfected individuals. Therefore, effective treatments for chronic HBV infection are required. In cell culture, nuclear hormone receptors have been shown to be essential for HBV pregenomic RNA synthesis and viral biosynthesis. Using a HBV transgenic mouse model of chronic HBV infection, the potential critical role of the nuclear hormone receptors, HNF4 and RXR-alpha plus PPAR-alpha, in regulating HBV transcription and replication in vivo will be investigated. If these nuclear hormone receptors are essential for viral biosynthesis in vivo, these ligand-dependent transcription factors should represent important targets for the development of antiviral agents. In addition, altering the level of expression of the HNF3 isoforms in cell culture and in vivo has been shown to inhibit HBV replication. The role of modulating cellular signal transduction pathways in determining the level of expression of the HNF3 isoforms in vivo and inhibiting HBV transcription and replication will be examined. Understanding the cellular targets of the signal transduction pathways that inhibit HBV synthesis should permit the rational design of antiviral agents. The transgenic mouse model of chronic HBV infection will be used to understand the role of transcriptional regulation in the generation and maintenance of HBV covalently closed circular (CCC) DNA in vivo. Inhibition of HBV CCC DNA synthesis is essential to viral clearance and the prevention of primary hepatocellular carcinoma in man. All of these studies are aimed at identifying possible targets for therapeutic intervention in chronic HBV infection.